Bipolar disorder affects 1-2% of the population. Numerous family and twin studies support a substantial genetic component, but the genetics is complex. Evidence has been reported suggesting that variants in the gene G protein receptor kinase 3 (GRK3) are associated with increased risk for disease. TDT analyses of two family sets showed excess transmission of two promoter DNA sequence variants with P value = 0.0019. GRK3 mediates homologous desensitization of a broad range of G-protein-coupled receptors, and hence may be an important component in the overall regulation of neurotransmitter signaling. Lymphocytes express GRK3 and regulate expression in response to activation of signaling. They thus provide the opportunity to study GRK3 and cell signaling in the context of native, intact chromosomes. In this proposal, model systems will be established in lymphoblastoid cell lines derived from subjects with bipolar disorder to study regulation of GRK3 expression and to assess homologous receptor desensitization, in response to activation of cell signaling by a variety of neurotransmitter and hormone ligands. Validity of these models will be tested in neuronal cell lines. Lymphoblastoid cell lines from subjects with bipolar disorder will then be tested for altered regulation of GRK3 expression, altered production of signaling second messengers, and altered homologous receptor desensitization. These measures of signaling dysregulation will be assessed for genetic association to GRK3 and for evidence of association to other genomic loci by genome wide quantitative trait linkage analysis. By these means the hypothesis will be tested that abnormalities in cellular endophenotypes involving signaling and receptor desensitization constitute risk endophenotypes for bipolar disorder.